Amino derivative of carboxy-alkoxy diphenyls



Patented Aug. 7, 1934 UNITED STATES AMINO DERIVATIVE OF CARBOXY-ALKOXYf DIPHENYLS -Walter GrChi-istiansen, Glen Ridge, N. J., and Adelbert W. Harvey, Pittsburgh, Pa., assignors to E. R. Squibb & Sons,

poration of New York Brooklyn N. Y.-, a cor- NoDrawing. Application Deoember 23, 1932, Serial No. 648,583 H 6 Claims. (Cl. 260-109) This invention relates to amino derivatives of carboxy-alkoxy-diphenyls such as the B-carboxy- 4-alkoxy-amino-diphenyls and salts thereof. More particularly, it refers to 3-carboxy-4- ethoxy-4-amino-diphenyl and 3-carboxy-4-butoxy-4-amino-diphenyl. The invention includes the method of producing amino derivatives of carboxy-alkoxy-diphenyls.

These new compounds are valuable as intermediates in the production of end products which have therapeutic value, particularly as local anesthetics. They may also have other uses.

The amino derivatives of carboxy-alkoxy-diphenyls may be prepared in various ways. It maybe possible, for example to form the amino derivative by reduction of an azo compound or to introduce the amino group directly by the reaction of ammonia under, pressure on a suitable halogen alkoxy or hydroxy derivative to form compounds such as 5-amino-3-carboxy-4- ethoxy-diphenyl or 5-amino-3-carboxy-4-hydl'oxy-diphenyl from which the desired alkoxy derivative may be, prepared by etherifying. In preparing 3-carboxy 4 alkoxy 4 amino diphenyl, we prefer to nitrate and etherify 3- carboxy i-hydroxy-diphenyl (which: may be prepared by the method disclosed in the 'application of A. W. Harvey, Serial No. 615,473, filed June 4, 1932, now Patent No. 1,941,207 of, Dec. 26, 1933) and then reduce the nitro group to form the amino derivative. The nitration may precede or iollow'the etherification. The reactions may, for example, be carried out as follows:

- The'following examples are'illustrative'of the process: u

or by any other suitable method of evaporation. Care should be taken to prevent absorption of carbon dioxide by thesolution or the wet mass during evaporation. Final drying of the phenolate is carried out in vacuo, about 10 mm. .at 180 C. for sometime, usually five hours, after nomore water is collected in an ice trap.

The dry pulverized phenolate is treated with carbon dioxide in an autoclave at approximately pounds per square inch to'iorm the sodium salt of 3-carboxy 4 hydroxy diphenyl'. The temperature is held at-110-120C., for-11 hour, increased to MSG-170 0., and held at the latter temperature for 3-4 hours. The reaction prodnot is placed in 3000-4000 cc.-of water, heated to boiling, and then preferably after filtering treated with carbon dioxide until no more 4- hydroxy-diphenyl is precipitated. The suspension is filtered to remove the unconvertedilhydroxy-diphenyl and the 3-carb'oxy-4 -hydroxydiphenyl is precipitated by acidification -with mineral acid. The productis thenfiltered off, washed with'water and dried;

214 grams of 3-carboxy 4-hydroxy-diphenyl is convertedinto the disodium derivative (sodium salt and sodium phenolate) by treatment with'80 grams of sodium hydroxide dissolved in 3000-4000 cc. of water. The mixture is boileduntil all of the 3-carboxy-4-hydroxy'-diphenyl has been dissolved and'is then evaporated to dryness. Final drying is conveniently carriedfout by. placing in an oven at -110 C. for several hours.- The NO: NH:

'dry-disodiurn compound is treated with 154 grams of ethyl sulfate, or more conveniently with a considerable excess over this amount, and heated for 3-4 hours at 145 0. During the early stages of heating, at 105-120 0., a small quantityof alcohol and ether is distilled off after which no.further distillation takes place Care must be taken to control the temperature to prevent decomposition of the ethyl sulfate with possible sul- The free acid, 3-carb0xy-14-ethoxy1diphenyl, .is

made from the ethyl ester by saponification with sodium hydroxide and precipitation with a mineral acid, such as hydrochloric acid. "This acid is purified by recrystallization from alcohol.

48.4 grams (0.2 mol.) of 3-carboxy-4-ethoxydiphenyl is dissolved in 175 cc. of glacial acetic sby Warming to :a temperature oi ITO-a0" C. The solution is .held :at HO- C. while :aslight excess raver-d2 anol. of nitric acid is added :very slowly during .-1.- -':2 hours; A saitisfactory yield was'obtaiine'dxhy adding 14.5 cc. zoinitfic acid (spa-gr; .1312) sdiluted withlil) -:c.c.1of :glacial :acetic acid, during two hours. As an alternative method the nitric :acid .may be added all .at once or. .seyeral relatively iarge proportions, .such asxtwenty to twenty-five percent :of the total amount. .;solution is preferably mechanically agitated "during the addition of the nitric acid, and :heating at 70-7715" 0. should be continued .=f or -112:honrs afiter ealibthe nitric .acid :has -.been:added.

mnicooling to .room temperature .s-carboxy-- ethoxwM-nitro-idiphenyl crystallizes the reaction mixture. it may be purifiedby mecry-stallization from alcohol. .The yield obtained (by separation from the reaction .mixture may be somewhat increased by recovery and purification lot-the :material which remainsein .solutionin the .acid. ,More hig ly nitrated compounds are present in the .aceticacidlliquor.

I Reduction pf .3-carboxy-4.- ethoxy-4'-nitro diphenyllto the corresponding 'iwamino derivative may be satisfactorily accomplished'by using powdered iron, with or without acid, and water or by maniac; reduction with hydrogen using a catalyst such as ,platinu n oxide. The latter methodhasfthe advantage of simplicity. v

1 gram 'of 3-'carboxy-4 -ethoxy-4-nitro-diphenyl' is xfissolvedinfdo cc. 'of absolute alcohol, tre'ated"with "0:05 gram of platinum oxide catalyst and the mixture agitated with hydrogen under a pressure otf 30 pounds per square inch until reduction .is-co'mplete. A' reaction; time of 1 hour is ample for completion of the reduction. The color of the solution will be (changed from yellow to practically colorless, and there will be a separation of axcolorless crystalline reaction product. I

The reduced compound, 3-{carboxy-4-ethoxy- 4' amino-diphenyl, recovered by filtration-of the warm alcoholic solution to remove the catalyst, followed by evaporation of the solvent. d ur ifica'tion "be -.caccomplished by.- zrecrystal- 'lizaition drom ailcohdl. a

"The compoun'd is obtainedfias colorless, .coarse nee'dlesjw hich are soluble in-ether, benzene, acetone and pther'orgarfic sol-vents.and as'thahydroturbine in warm dilute hydrochloric acid :and .as thealkali metal salt in water. "The compound isusiul-"as an intermediate :in the preparation oif' local anestheticsmr other synthetic derivatives.

It has a melting point of 177.5 to 178.5 C. (corrected).

Example 2 "42.8 grams 0.2 mol.),iof 3-carboxy-4 -hydroxydiphenyl is converted into thedisodiiun derivative bytreatment with 16 grams of sodium hydroxide dissolved in 600-800 cc. of water. The

mixture is boiled until all of the 3-carboxy-4- hydroxyediphenyl has .been dissolved and is then evaporated to dryness. Final drying is conveniently carried out by placing in an oven at 105- .1140" C. tor several hours.

The dry disodiumcompound is treated with an excess over 5438 grams (0.4 mol.) of n-butyl bromide and heated preferably in a closed vessel vina loath.m;aintained at 130 C. for five hours. After cooling, the n-butyl ester of 3-carboxy-4- n-butoxy-diphenyl and excess of n-butyl-bromide is filtered from the by-product sodium bromide and the excess of n-butyl bromide removed by distillation. 'The residue consists principally of the n-butyl ester of. '3'-.carboXy--,4:n-buitoxikdiphenyl. 1 i

The free acid, 3ecarboxyrl n-butoxyediphenyl, is obtained by saponifica'tion of its n-ibu'tyl ester with dilute aqueous-alcoholic solution of sodium hydroxide and precipitation of the free ,acid'from the resulting sodium salt by acidification with mineral acid, such as hydrochloric acid. it is preferable .to remove the greater part of'the alcohol Ifrom the ,saponi-fica'tion mixture before the acid precipitation. V f

The compound may be filtered off,' ,drie.d' and purified .by crystallization from a mixture .of benzene and petroleum ether, .or 'fromjal proxi- .ma'tly .60 percent alcohol. [The ,pure material crystallizes in pure white crystals with a melting point of .83..5-8415. 2C. .(corrected'),

The .compoundiis, soluble in alcohol, ether, benzene, chloroform and several other organicsolvents. r

27.0 grams (L0.1..mol.) of i3-carboXy-A-nbutoxy-diphenyl is dissolvedin 135 cc...of ,glacial acetic .acid by warming to '70-.80, The solution, after cooling to, .45.50 .C. is treated with 8.1 .cc. .(a slight excess .overxO .1 moll) of, nitric acid :(sp. gr.=.-l.42). in .217. cc. of glacial acetic acid. The temperature is then raised to 909 .C. during .one .hour and held at .90-100 .C. for 23 .hours.

. .nitra-ted. reaction product, .3-carboxy-4nbutoxy-A -nitro diphenyl is recoyerediby diluting .the reaction mixture with 100 .cc. .of Zhotwater and allowing to stand until crystallization is complete. The product may be purified by crystallization from percent alcohol ifollowed by rezcnystatllization' .from a .mixture" of ben ene and petroleum ether. An :average yield of about 50 percent maybe obtained by the above method and this may be increased by recovery and purification of the material which remains in solution in the diluted acetic acid mother liquor.

The compound crystallizes fromza mixture of benzene/and petroleum ether iniine, pale yellow needles with a melting point of 102-103 C. (corrected). v Reduction. 10f .'13ecarboxy-aen butoxyn'enitrodiphenyl to the corresponding 4-amino.aderivative may be done satisfactorily by using powdered iron, with or without acid, and. water or by catalytic reduction with hydrogen using a :catalyst such as platinum oxide'. 'The"'latte'r method 'has theadvantage o'fsimplicity.

1 gram -:of 3 carboxy=4-nebutoxy-4 enitrodiphenyl iisdissolvediin .60 sec. of :absolute alcohol,

also

treated with 0.05 gram of platinum oxide catalyst and the mixture agitated with hydrogen under a pressure of 30 pounds per square inch until reduction is complete. A reaction time of one hour is ample for completion of the reduction. The color of the solution will be changed from yellow to practically colorless, and there will be a separation of a colorless crystalline reaction product.

The reduced compound, 3 carboxy 4-nbutoxyi-amino-ld*iphenyl, is recovered by filtration of the warm alcoholic solution to remove the catalyst, followed by evaporation of the solvent. Purification may be accomplished by recrystallization from alcohol.

The compound is obtained as colorless, coarse needles, which are soluble in ether, benzene, acetone and other organic solvents and as the hydrochloride in warm dilute hydrochloric acid and as the alkali metal salt in water. The compound is useful as an intermediate in the preparation of local anesthetics or other synthetic derivatives. It has a melting point of 163.0 to l63.8 C. (corrected).

Other amino derivatives may be similarly prepared from other carboxy-alkoxy-diphenyls, for example, 3 carboxy 2 alkoxy-diphenyls. Instead of preparing the ethyl or butyl ether of 3 carboxy-4hydroxy4'-amino-diphenyl, other ethers may be formed by a similar reaction using other alkyl halides or salts such as methyl sulfate in the preparation of the methyl ether and alkyl sulfites or alkyl para toluene sulfonates in the preparation of ethers containing more than two carbon atoms in the alkoxy group.

Various metallic salts may be prepared by neutralizing the acid with metal bases. Amine salts are formed by neutralization with a suitable acid in aqueous solution or, for example, by

COOX

where R is an alkyl group, X is hydrogen or a metal capable of forming a metal base, and Y is the amino group or the amino group neutralized by an acid.

2. A 4-alkoxy-4'-amino-diphenyl having in the 3-position a carboxy group neutralized with a metal which is capable of forming a metal base.

3. The method of preparing amino derivatives of compounds of the group consisting of 3-carboxy 4 alkoxy diphenyls and 3-carboxy-2- alkoxy-diphenyls which comprises esterifying a compound of the group consisting of the 3- carboxy-4-hydroxy-diphenyls and the B-carboxy- 2-hydroxy-diphenyls and alkylating the hydroxy group then saponifying, nitrating and reducing,

4. 3-carboxy-4-alkoxy-4-amino-diphenyls.

5. 3-carboxy-4-ethoxy-4-amino-diphenyl.

6. 3-carb0xy4-butoxy-4'-amino-dipheny1.

WALTER G. CHRISTIANSEN. ADELBERT W. HARVEY. 

